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Clinical Trial Results:
HYCOVID - Hydroxychloroquine versus placebo chez les patients ayant une infection COVID-19 à risque d’aggravation secondaire : étude prospective multicentrique randomisée en double aveugle

Summary
EudraCT number	2020-001271-33
Trial protocol	FR
Global end of trial date	18 Jun 2020

Results information
Results version number	v1(current)
This version publication date	18 Apr 2022
First version publication date	18 Apr 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

49RC20_0071

ISRCTN number

US NCT number

NCT04325893

WHO universal trial number (UTN)

Sponsor organisation name

CHU Angers

Sponsor organisation address

4 rue Larrey, Angers, France, 49933

Public contact

chef de projets, CHU Angers, +33 0241353637, DRCI-Promotion-Interne@chu-angers.fr

Scientific contact

chef de projets, CHU Angers, +33 0241353637, DRCI-Promotion-Interne@chu-angers.fr

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

14 Jul 2020

Is this the analysis of the primary completion data?

Yes

Primary completion date

04 Jun 2020

Global end of trial reached?

Yes

Global end of trial date

18 Jun 2020

Was the trial ended prematurely?

Yes

Main objective of the trial

L’objectif principal est d’évaluer l’efficacité de l’hydroxychloroquine versus placebo sur le taux de décès ou de recours à une ventilation invasive chez les patients ayant une infection COVID-19 à haut risque d’aggravation.

Protection of trial subjects

Réalisation systématique d’un ECG après la dose de charge, puis toutes les 48 à 72 heures en cas de prise concomitante de médicaments à risque. Le rapport bénéfice/risque n'a pas été modifié au cours de l'étude. Le comité de surveillance indépendant n'a pas demandé de modifications. Les inclusions ont été suspendues le 26/05/2020, suite à la parution de l'étude parue dans le Lancet qui a conduit le Comité Scientifique de Solidarity à réaliser une analyse intermédiaire. 3 informations de sécurité ont été transmises aux investigateurs (10/04/2020 suite aux retours des centres de pharmacovigilance sur le risque avéré de troubles du rythme ventriculaire graves, 24/04/2020 suite à une information de l'EMA, et 10/05/2020 suite à l'information par l'Agence Espagnol des Médicaments d'un signal de sécurité sur des troubles neuropsychiatriques).

Background therapy

Evidence for comparator

Actual start date of recruitment

02 Apr 2020

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 257

Worldwide total number of subjects

257

EEA total number of subjects

257

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Ouverture de 48 centres investigateurs sur l'ensemble du territoire national français. 257 patients ont été inclus dans 42 centres.

Screening details

1822 patients ont été screenés. 1568 patients n'ont pas été inclus pour défaut de critères d'inclusion (1080) et/ou de non inclusion (681), 54 patients ont refusé de participer à l'étude

Period 1 title

overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

Plaquenil et placebo

Are arms mutually exclusive

Yes

Placebo

Arm description

Placebo

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

dose cumulée 4 000 mg

Hydroxychloroquine

Arm description

bras expérimental

Arm type

Experimental

Investigational medicinal product name

Plaquenil

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

800mg à J1 400mg de J2 à J9

Number of subjects in period 1 ^[1] ^[2]	Placebo	Hydroxychloroquine
Started	124	125
Completed	122	126
Not completed	2	0
Protocol deviation	2	-
Joined	0	1
Transferred in from other group/arm	-	1

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: I confirm 2 patients "placebo" did not start the treatment, 1 of them begin hydroxychloroquine treatment
[2] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
Justification: I confirm. 2 patients "placebo" did not start the treatment, 1 of them begin hydroxychloroquine treatment

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Placebo

Reporting group title

Hydroxychloroquine

Reporting group description

bras expérimental

Reporting group values	Placebo	Hydroxychloroquine	Total
Number of subjects	124	126	250
Age categorical
Units: Subjects
Adults (18-64 years)	43	40	83
From 65-84 years	37	53	90
85 years and over	44	33	77
Age continuous
Units: years
median (full range (min-max))	78 (57 to 87)	76 (60 to 85)	-
Gender categorical
Units: Subjects
Female	68	61	129
Male	56	65	121

Subject analysis set title

Modified intention to treat

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

There were no significant differences between the two groups in demographic characteristics at inclusion, time from first signs of infection to inclusion, distribution of risk factors for adverse outcomes, and treatments received at inclusion

Subject analysis sets values	Modified intention to treat
Number of subjects	250
Age categorical
Units: Subjects
Adults (18-64 years)	82
From 65-84 years	89
85 years and over	77
Age continuous
Units: years
median (full range (min-max))	77 (58 to 86)
Gender categorical
Units: Subjects
Female	129
Male	121

End points

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Reporting group title

Placebo

Reporting group description

Placebo

Reporting group title

Hydroxychloroquine

Reporting group description

bras expérimental

Subject analysis set title

Modified intention to treat

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Primary: Rate of mortality and use of invasive ventilation among among non-severe COVID-19 patients at a high risk of complicated course

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End point title

Rate of mortality and use of invasive ventilation among among non-severe COVID-19 patients at a high risk of complicated course

End point description

End point type

Primary

End point timeframe

Day 14

End point values	Placebo	Hydroxychloroquine
Number of subjects analysed	123	124
Units: percentage
number (not applicable)	123	124

Analyse statistique

Statistical analysis description

Les variables quantitatives seront décrites en moyenne +/- écart-type ou médiane et intervalle interquartile pour les distributions non-normales. Les variables qualitatives seront décrites en effectif et pourcentage. Les comparaisons de moyennes seront réalisées avec le test t de Student (test de Mann-Whitney si nécessaire) et les comparaisons de pourcentages avec le test du Chi2 (test exact de Fisher si nécessaire). L’analyse du critère de jugement principal sera réalisée en ITT

Comparison groups

Placebo v Hydroxychloroquine

Number of subjects included in analysis

247

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.82

Method

Chi-squared

Confidence interval

Adverse events

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Timeframe for reporting adverse events

Day 28

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.1

Reporting group title

Placebo

Reporting group description

Placebo

Reporting group title

Hydroxychloroquine

Reporting group description

Serious adverse events	Placebo	Hydroxychloroquine
Total subjects affected by serious adverse events
subjects affected / exposed	18 / 122 (14.75%)	23 / 126 (18.25%)
number of deaths (all causes)	6	4
number of deaths resulting from adverse events	6	4
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Small intestine carcinoma
subjects affected / exposed	1 / 122 (0.82%)	0 / 126 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Vascular disorders
Ischaemic stroke
subjects affected / exposed	0 / 122 (0.00%)	1 / 126 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Subdural haematoma
subjects affected / exposed	1 / 122 (0.82%)	0 / 126 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 122 (1.64%)	0 / 126 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	1 / 122 (0.82%)	0 / 126 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Malaise
subjects affected / exposed	1 / 122 (0.82%)	0 / 126 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 122 (0.00%)	1 / 126 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 122 (0.82%)	0 / 126 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea exertional
subjects affected / exposed	0 / 122 (0.00%)	1 / 126 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 122 (0.00%)	1 / 126 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	1 / 122 (0.82%)	0 / 126 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	1 / 122 (0.82%)	0 / 126 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pulmonary embolism
subjects affected / exposed	3 / 122 (2.46%)	4 / 126 (3.17%)
occurrences causally related to treatment / all	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 0
Respiratory failure
subjects affected / exposed	0 / 122 (0.00%)	1 / 126 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 122 (0.82%)	0 / 126 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Disorientation
subjects affected / exposed	1 / 122 (0.82%)	0 / 126 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric decompensation
subjects affected / exposed	0 / 122 (0.00%)	1 / 126 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 122 (0.00%)	2 / 126 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	0 / 122 (0.00%)	1 / 126 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Incorrect product administration duration
subjects affected / exposed	0 / 122 (0.00%)	1 / 126 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Product administration error
subjects affected / exposed	0 / 122 (0.00%)	3 / 126 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	2 / 122 (1.64%)	0 / 126 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 122 (0.82%)	1 / 126 (0.79%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	1 / 122 (0.82%)	0 / 126 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 122 (0.82%)	0 / 126 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Conduction disorder
subjects affected / exposed	1 / 122 (0.82%)	0 / 126 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Palpitations
subjects affected / exposed	0 / 122 (0.00%)	1 / 126 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Stress cardiomyopathy
subjects affected / exposed	0 / 122 (0.00%)	1 / 126 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular extrasystoles
subjects affected / exposed	0 / 122 (0.00%)	2 / 126 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	1 / 122 (0.82%)	0 / 126 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cognitive disorder
subjects affected / exposed	0 / 122 (0.00%)	1 / 126 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Partial seizures
subjects affected / exposed	0 / 122 (0.00%)	1 / 126 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 122 (0.00%)	2 / 126 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 122 (0.00%)	1 / 126 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Diverticulum intestinal
subjects affected / exposed	1 / 122 (0.82%)	0 / 126 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal perforation
subjects affected / exposed	1 / 122 (0.82%)	0 / 126 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Urticaria
subjects affected / exposed	1 / 122 (0.82%)	0 / 126 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 122 (0.00%)	2 / 126 (1.59%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 122 (0.00%)	1 / 126 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abscess
subjects affected / exposed	0 / 122 (0.00%)	1 / 126 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 122 (0.00%)	1 / 126 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung abscess
subjects affected / exposed	0 / 122 (0.00%)	1 / 126 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Adult failure to thrive
subjects affected / exposed	1 / 122 (0.82%)	0 / 126 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Dehydration
subjects affected / exposed	0 / 122 (0.00%)	1 / 126 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Hypokalaemia
subjects affected / exposed	0 / 122 (0.00%)	1 / 126 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Placebo	Hydroxychloroquine
Total subjects affected by non serious adverse events
subjects affected / exposed	50 / 122 (40.98%)	46 / 126 (36.51%)
Cardiac disorders
heart rythm
subjects affected / exposed	50 / 122 (40.98%)	46 / 126 (36.51%)
occurrences all number	92	118

More information

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Were there any global substantial amendments to the protocol? Yes

01 Apr 2020

Mise à jour des centres investigateurs

09 Apr 2020

Ajout de 10 centres et changement de l’Investigateur Principal du CHU de Rennes

21 Apr 2020

Précision sur les critères d’inclusions (ajout de délai « dans les dernières 24h ») Ajout paragraphe pour la CNIL : transmission des consentements par fax aux ARC pour s’assurer qu’il n’y ait pas de déviation critique

26 May 2020

Suspension des inclusions sur la base d’un projet de suspension des essais avec hydroxychloroquine par l’ANSM

08 Jun 2020

Modifications des lettres d’information suite à l’amendement 5, Modification du paragraphe statistique Ajout du lien pour le Thésaurus ANSM (traitement interagissant avec l’hydroxychloroquine)

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
26 May 2020	Suspension des essais sur l'hydroxychloroquine par l'ANSM Fin de la vague Covid suite au confinement	-

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
HYCOVID - Hydroxychloroquine versus placebo chez les patients ayant une infection COVID-19 à risque d’aggravation secondaire : étude prospective multicentrique randomisée en double aveugle

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Rate of mortality and use of invasive ventilation among among non-severe COVID-19 patients at a high risk of complicated course

Primary: Rate of mortality and use of invasive ventilation among among non-severe COVID-19 patients at a high risk of complicated course

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: HYCOVID - Hydroxychloroquine versus placebo chez les patients ayant une infection COVID-19 à risque d’aggravation secondaire : étude prospective multicentrique randomisée en double aveugle

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Rate of mortality and use of invasive ventilation among among non-severe COVID-19 patients at a high risk of complicated course

Primary: Rate of mortality and use of invasive ventilation among among non-severe COVID-19 patients at a high risk of complicated course

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
HYCOVID - Hydroxychloroquine versus placebo chez les patients ayant une infection COVID-19 à risque d’aggravation secondaire : étude prospective multicentrique randomisée en double aveugle